International Patent Application PCT/HU90/00076 describes tetrahydropyridine derivatives structurally related to the compounds of the invention which are said to have antiamnesic activity. In contrast to the present compounds, however, said compounds can be considered as .beta.- or .tau.-amino ketone compounds the nitrogen atom of which is closed as a ring member into said substituted tetrahydropyridine ring.
The invention relates to novel, therapeutically active N-hydroxyalkyl-substituted 1,2,3,6-tetrahydropyridine and piperidine derivatives of the formula ##STR2## wherein A is hydrogen or halogen; alkoxy; cyano; phenyl; phenyl monosubstituted by halogen; benzyl; benzyl monosubstituted by halogen; 2-phenylethyl monosubstituted by halogen on the phenyl moiety; or 2-picolyl group;
B is hydrogen; alkoxy or nitro; PA0 D is hydrogen, halogen; or alkoxy; or PA0 B and D together are a --CH.dbd.CH--CH.dbd.CH-- group; PA0 R is hydrogen; alkyl or phenyl; PA0 G is hydrogen; PA0 I is hydrogen or hydroxy; or PA0 G and I together are a single chemical bond; PA0 E is for hydrogen, halogen, alkoxy or trifluoromethyl; and PA0 m is 0, 1 or 2, PA0 m is 0 or 2, or both G and I are hydrogen, when A is benzyl or halogen-monosubstituted benzyl; and PA0 m is 1, when A is 2-picolyl, PA0 1-[4-(4-chlorobenzyl)phenyl]-2-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)ethan ol, PA0 1-[4-(4-chlorobenzyl)phenyl]-3-(4-phenyl-1-piperidyl)propanol, PA0 1-[4-(4-chlorobenzyl)phenyl]-4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butan ol, PA0 3-[4-(4-fluorophenyl)-1-piperidyl]-1-(1,1'-biphenyl-4-yl)propanol, PA0 3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]-1-(2,4-dichlorophenyl)p ropanol. PA0 b) reacting a compound of formula (III) with an acetophenone or propiophenone of formula ##STR6## wherein R.sup.1 is hydrogen or methyl, in the presence of formaldehyde under conditions of the Mannich's reaction [Arch. Pharm. 250, 647 (1912)] to obtain compounds of formula (II), wherein m is 1.
with the proviso that:
as well as their acid addition salts.
Alkyl group as used herein either in itself or as a moiety of another group, is a straight or branched chain saturated hydrocarbon group containing 1-10 carbon atoms such as methyl, ethyl, n- and isopropyl, n-, o-, sec- and tert-butyl groups as well as the various pentyl, hexyl, heptyl, octyl, nonyl and decyl groups. C.sub.1-6 alkyl groups are preferred, C.sub.1-4 alkyl groups are more preferable and methyl group is particularly favorable.
Halogen may mean fluorine, chlorine, bromine or iodine.
The following compounds are particularly preferred:
The present invention also relates to a pharmaceutical composition for treating conditions selected from hypoxia and ischaemia comprising an amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof effective in treating such conditions and a pharmaceutically acceptable carrier.
Furthermore, the present invention also relates to a process and intermediates for the preparation of the compounds of formula (I), as well as acid addition salt thereof.
Additionally, the present invention relates to a process for the preparation of pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.
The present invention also relates to a method of treatment, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically accaptable acid addition salt thereof to a mammal (including man) for strengthening its tolerance against hypoxic and/or ischaemic conditions as well as for treating degenerative and functional disturbances arising from hypoxic and/or ischaemic insults.
Surprisingly, it has been found that the compounds of formula (I) are capable to protect the brain from the cognitive function-injuring effect of various harmful conditions, e.g. hypoxia and/or ischaemia; or they are useful to enhance the tolerance against hypoxic and/or ischaemic conditions, respectively as well as to treat degenerative and functional disturbances arising from hypoxic and ischaemic insults.
The biological effects of compounds according to the invention are hereinafter illustrated by using the following test methods.
Male CFLP mice (from the Hungarian stock LATI) weighing 24-26 g each and spontaneously hypertensive (SH) male rats weighing 160-180 g each, respectively were used in these investigations. The compounds to be tested were orally administered in a volume of 10 ml/kg one hour prior to starting the experiment.